The malarial fever response—pathogenesis, polymorphism and prospects for intervention

Kwiatkowski, Dominic; Bate, Clive; Scragg, Ian G.; Beattie, Pauline; Udalova, Irina A.; Knight, Julian C.

doi:10.1080/00034983.1997.11813171

Cited by 31 publications

(28 citation statements)

References 45 publications

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“…P. falciparum-derived hemozoin binds to TLR-9 on murine myeloid DCs that subsequently produce large amounts of TNF-␣ (60). Intriguingly, in our study, TNF-␣ was up-regulated before any significant schizont rupture leading us to speculate that, in contrast to what has previously been suggested (6,7,46), large-scale schizont rupture may not be essential for induction of innate immune responses to malaria. Possible alternative explanations include activation of monocyte-macrophages following phagocytosis of iRBC or leakage of soluble molecules from damaged-but still intact-iRBC.…”

Section: Discussioncontrasting

confidence: 47%

“…The similarity in the kinetics of the LPS and iRBC responses strongly suggested that iRBC must be able to trigger innate responses immediately on being added to the PBMC cultures. This was unexpected because it is generally assumed that schizont rupture is the key event in triggering innate immune responses (6,7,46), and large-scale schizont rupture did not occur until 3-6 h after adding of iRBC to the cultures (Fig. 6a).…”

Section: In Vitro Cytokine Responses To P Falciparum-infected Rbcmentioning

confidence: 94%

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Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

Walther

Woodruff

Edele

et al. 2006

The Journal of Immunology

141

118

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Taking advantage of a sporozoite challenge model established to evaluate the efficacy of new malaria vaccine candidates, we have explored the kinetics of systemic cytokine responses during the prepatent period of Plasmodium falciparum infection in 18 unvaccinated, previously malaria-naive subjects, using a highly sensitive, bead-based multiplex assay, and relate these data to peripheral parasite densities as measured by quantitative real-time PCR. These data are complemented with the analysis of cytokine production measured in vitro from whole blood or PBMC, stimulated with P. falciparum-infected RBC. We found considerable qualitative and quantitative interindividual variability in the innate responses, with subjects falling into three groups according to the strength of their inflammatory response. One group secreted moderate levels of IFN-γ and IL-10, but no detectable IL-12p70. A second group produced detectable levels of circulating IL-12p70 and developed very high levels of IFN-γ and IL-10. The third group failed to up-regulate any significant proinflammatory responses, but showed the highest levels of TGF-β. Proinflammatory responses were associated with more rapid control of parasite growth but only at the cost of developing clinical symptoms, suggesting that the initial innate response may have far-reaching consequences on disease outcome. Furthermore, the in vitro observations on cytokine kinetics presented here, suggest that intact schizont-stage infected RBC can trigger innate responses before rupture of the infected RBC.

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Section: Discussioncontrasting

confidence: 47%

Section: In Vitro Cytokine Responses To P Falciparum-infected Rbcmentioning

confidence: 94%

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

Walther

Woodruff

Edele

et al. 2006

The Journal of Immunology

141

118

View full text Add to dashboard Cite

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“…Moreover, complementing the results of McGuire et al (1994), we found no significant difference in PCV levels between infants with different TNF ␣ promotor genotypes. The relationship between TNF2 allele and elevated TNF ␣ levels is still controversial (Kwiatkowski et al 1997) and a protective advantage of heterozygous infants against malaria infection or morbidity appears to be rather unlikely. However, a balanced polymorphism might exist for the TNF ␣ promotor polymorphism, because heterozygotes appear to have a more effective response to other infectious agents.…”

Section: Discussionmentioning

confidence: 99%

Malaria infection and morbidity in infants in relation to genetic polymorphisms in Tanzania

Stirnadel

Stöckle

Felger

et al. 1999

Tropical Med Int Health

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SummaryTo investigate the effects of host polymorphisms on malaria morbidity and infection, the frequency distributions of TNF ␣ promotor gene and sickle cell trait were studied in infants in an area highly endemic for Plasmodium falciparum transmission in Tanzania. Differences in parasite prevalence, density, febrile episodes with and without parasitaemia, PCV levels and the frequencies of different MSP-2 parasite infections were assessed by genotype. The frequency of the TNF ␣ promotor allele 2 was 0.09, and the trait was in Hardy-Weinberg equilibrium. There were no differences in malariametric indices between infants with the normal TNF ␣ promoter gene and those who were heterozygous for this trait. Infants heterozygous for the TNF ␣ promotor gene appeared to have fewer febrile episodes when they were free of parasites. The two infants homozygous for the TNF ␣ promoter allele 2 had both a much higher incidence of fever, independently of parasitaemia, than the average for the other genotypes. The frequency of the sickle cell allele S was 0.06 and the trait was also in Hardy-Weinberg equilibrium. Infants heterozygous for the sickle cell trait had significantly lower parasite densities, but similar prevalence, and MSP-2 infections compared to infants with normal haemoglobin. PCV levels, and the incidence of febrile episodes both with and without parasitaemia were also similar. In contrast to the sickle cell trait, the TNF ␣ promotor polymorphism appeared not to have any protective effect on malaria in this study, and its importance in other unspecified fever-causing diseases in this population needs further investigation.keywords Plasmodium falciparum malaria, tumour necrosis factor-␣ promotor polymorphism, sickle-cell trait, infants correspondence Heide A. Stirnadel,

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“…31 The mechanisms of asymptomatic parasitemia/anti-disease immunity/malaria tolerance noted in infancy and older children are not clear. 31 Maternally derived IgG in infancy 32 and antibodies to toxin in older children 33,34 have been invoked as potential mediators. Age-dependent changes in innate immunity, 6,35,36 including those we have shown with NO production, may also be important.…”

Section: Discussionmentioning

confidence: 99%

Effects of age and parasitemia on nitric oxide production/leukocyte nitric oxide synthase type 2 expression in asymptomatic, malaria-exposed children.

Anstey¹,

Weinberg²,

Wang³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. Age appears to influence not only the acquisition of clinical immunity to malaria but also the susceptibility to and clinical manifestations of severe malaria. Asymptomatic malaria-exposed Tanzanian children have high production of nitric oxide (NO) and universal expression of leukocyte NO synthase type 2 (NOS2), which may protect against disease. To determine the effects of age and parasitemia on NO production, we measured urine and plasma NO metabolites and leukocyte NOS2 expression in 45 fasting, asymptomatic, malaria-exposed children of different ages, stratifying parasitemia by thick film and polymerase chain reaction (PCR) analysis. Although NO production was significantly higher in thick film-positive children than in thick film-negative children, after adjusting for age and gender, we were unable to detect a difference in NO production in thick film-negative children between those who were PCR positive and PCR negative. The relationship between age and NO production was determined using a generalized additive model adjusted for the effects of gender and parasitemia. Production of NO using all three measures was highest in infancy, decreasing after the first year of life, and then increasing again after 5 years of age. This pattern of age-related NO production is the reverse of the pattern of age-related morbidity from cerebral malaria in coastal Tanzanian children. Elevated production of NO in both infants and older children may be related to age per se and malaria infection respectively, and may be one of the mediators of the anti-disease immunity found most commonly in these two age groups.Nitric oxide (NO) mediates a diverse array of physiologic and pathologic processes, and appears to be an important mediator of the protective immune response to all stages of Plasmodium infections. 1 We have recently shown in Tanzanian children that systemic NO production and mononuclear cell (MNC) expression of the inducible isoform of NO synthase (NOS2) are inversely related to malaria disease severity. Although suppressed in cerebral malaria, systemic NO production/MNC NOS2 expression was universally increased in healthy, asymptomatic malaria-exposed children with or without parasitemia.2 Nitric oxide production/MNC NOS2 expression was higher in those asymptomatic children with parasitemia found on thick film examination, suggesting that NO production in these children may in part be due to the known ability of parasites to induce macrophage NOS activity.3,4 However, the majority of the asymptomatic children with constitutive expression of NOS2 were thick film negative, raising the possibility that NOS2 expression was due to parasitemia below the detection limits of microscopy, subclinical infection with other pathogens, or age-related physiologic NOS2 expression in childhood.Age appears to influence not only the acquisition of clinical immunity to malaria but also the susceptibility to and clinical manifestations of severe malaria. [5][6][7] Because NO production has been linked with host protection in ...

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The malarial fever response—pathogenesis, polymorphism and prospects for intervention

Cited by 31 publications

References 45 publications

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

Malaria infection and morbidity in infants in relation to genetic polymorphisms in Tanzania

Effects of age and parasitemia on nitric oxide production/leukocyte nitric oxide synthase type 2 expression in asymptomatic, malaria-exposed children.

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